PROJECT SUMMARY Alzheimer's disease (AD), Parkinson's' Disease (PD) and related disorders (RD) of the brain, are often linked to the loss of specific subtypes of neurons at the onset of the disease process. Therapeutic strategies aimed at promoting the survival, or replacing, disease-associated cell types is therefore of great interest. In particular, the loss of ?cholinergic? neurons in a region of the brain called the forebrain has been implicated as being causative for memory dysfunction in AD. Similarly, the loss of midbrain dopaminergic neurons causes PD. Regenerative medicine seeks to solve the problem of selective cell loss by replacing the cells that are missing ?the end goal being restoring lost functions to patients versus delaying the disease process. Two regenerative therapeutic strategies are envisioned: 1) transplantation of new `replacement' cells into the brain, and 2) local regeneration of lost cells from endogenous adult stem cells within the brain itself. Progress is being made regarding transplantation strategies for replacing lost neurons. However, all surgical procedures incur significant risks and there are a significant number of unknowns regarding the relative benefits versus pitfalls of stem cells grown in laboratory dishes, the source of new cells for transplantations. Thus, there is currently a substantial need for experimental systems that can help to de-risk cell transplantation procedures for regenerative medicine. Similarly, there is a clear and present need for experimental systems that can enable exploration of the therapeutic potential of adult neural stem cells as a means of replacing lost cells locally, through endogenous repair mechanisms that remain dormant in the absence of therapeutic intervention. We propose to address these resource deficits by developing novel inducible and titratable system for modeling AD and PD across multiple animal model systems, including: mouse, zebrafish and cultured human `organoids' (stem cell- derived tissues grown in culture dishes). Our approach to neurodegenerative disease modeling is specifically designed to facilitate 1) de-risking of human stem cell transplantation procedures, and 2) comprehensive dissection of the regenerative potential of adult neural stem cells. These new resources will simultaneously address current unmet needs and add significant experimental functionality to the AD, PD, and RD research landscape more broadly. More specifically, the proposed disease models will facilitate: 1) improved temporal resolution of system-wide responses to neuronal loss, and 2) large-scale phenotypic drug discovery in vivo, i.e., identification of neuroprotective and regeneration-promoting small molecules directly in living disease models. The proposed AD and PD disease models, as well as analogous strategies for modeling additional RD, will be made freely available to the research community in the hopes of advancing the development of transformative new therapies for patients with debilitating neurodegenerative disorders.